Complications of natural rubella infection and immunization with attenuated rubella vaccine have been reported. The etiology and possible molecular mechanisms underlying chronic rubella virus (RV) infection are presently unclear and incidence of such infections emphasizes the importance of this problem. To understand the mechanisms of RV RNA replication and pathogenicity, we are analyzing the function of both the conserved sequence elements and their interaction with host and viral encoded proteins. Sequences at the 5' and 3' end of RV genomic RNA, which can form stable stem-loop (SL) structures, are necessary for translation of viral proteins and for negative-strand RNA synthesis. We have identified the 5' (+) SL RV RNA binding protein a homologue of Ro/SS-A antigen by immuno-reactivity and by the ability of cytoplasmic RNA (hY3RNA), known to interact with Ro/SS-A antigen, to compete for the binding activity. The 3 '(+) SL RV RNA interacts specifically with cytosolic proteins found in African green monkey kidney cells (Vero 76) which are permissive for rubella virus replication. We have purified the binding protein from Vero 76 cells and identified it as a homologue of human calreticulin both by amino acid sequence similarity and by immune cross-reactivity. We have designated the host protein as simian calreticulin. This protein is a phosphoprotein and the post-translation modification is obligatory for RNA binding. The degree of phosphorylation increases upon rubella virus infection and it correlates with enhanced high affinity binding to the RV 3' (+) SL RNA. The significance of both Ro/SS-A antigen and calreticulin interaction with RV RNA is of clinical interest because antibodies to these proteins have been found in majority of autoimmune diseases. Currently, the role of both the Ro/SS-A antigen and calreticulin in rubella virus replication is being investigated which may have some bearing on the etiology of chronic rubella arthropathy.